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Hypercapnia attenuates ventilator-induced diaphragm atrophy and modulates dysfunction.

Critical care (London, England) (2014-02-11)
Willem-Jan M Schellekens, Hieronymus W H van Hees, Matthijs Kox, Marianne Linkels, Gilberto L Andrade Acuña, P N Richard Dekhuijzen, Gert Jan Scheffer, Johannes G van der Hoeven, Leo M A Heunks
ABSTRACT

Diaphragm weakness induced by prolonged mechanical ventilation may contribute to difficult weaning from the ventilator. Hypercapnia is an accepted side effect of low tidal volume mechanical ventilation, but the effects of hypercapnia on respiratory muscle function are largely unknown. The present study investigated the effect of hypercapnia on ventilator-induced diaphragm inflammation, atrophy and function. Male Wistar rats (n = 10 per group) were unventilated (CON), mechanically ventilated for 18 hours without (MV) or with hypercapnia (MV + H, Fico2 = 0.05). Diaphragm muscle was excised for structural, biochemical and functional analyses. Myosin concentration in the diaphragm was decreased in MV versus CON, but not in MV + H versus CON. MV reduced diaphragm force by approximately 22% compared with CON. The force-generating capacity of diaphragm fibers from MV + H rats was approximately 14% lower compared with CON. Inflammatory cytokines were elevated in the diaphragm of MV rats, but not in the MV + H group. Diaphragm proteasome activity did not significantly differ between MV and CON. However, proteasome activity in the diaphragm of MV + H was significantly lower compared with CON. LC3B-II a marker of lysosomal autophagy was increased in both MV and MV + H. Incubation of MV + H diaphragm muscle fibers with the antioxidant dithiothreitol restored force generation of diaphragm fibers. Hypercapnia partly protects the diaphragm against adverse effects of mechanical ventilation.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
DL-ジチオトレイトール 溶液, BioUltra, for molecular biology, ~1 M in H2O
Supelco
DL-ジチオトレイトール 溶液, 1 M in H2O
Sigma-Aldrich
Anti-Beclin-1 antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Anti-HNE Fluorophore Rabbit pAb, liquid, Calbiochem®